Design, Synthesis, and Anti-inflammatory Activity Evaluation for Hydrazide-Based HDAC6 Targeted Protein Degraders.

Histone deacetylase 6 (HDAC6) modulates inflammatory signaling through both its catalytic domain and its zinc-finger ubiquitin-binding domain, which makes inhibiting HDAC6 a promising anti-inflammatory therapeutic strategy. Previously, we developed a series of hydrazide-based HDAC6-selective inhibitors with favorable pharmacokinetic properties. Based on this, we herein report the rational design and synthesis of first-in-class hydrazide-based HDAC6 degraders that eliminate both the catalytic and zinc-finger ubiquitin-binding domain. Among them, compound 22f (DC50 = 13.4 nM) potently and selectively degraded HDAC6 via the ubiquitin-proteasome pathway without impacting other HDAC subtypes and CRBN neosubstrates. 22f inhibits NLRP3 inflammasome assembly and activation, as well as blocks NF-κB signaling, thereby reducing the transcription and release of key inflammatory factors. In a DSS-induced mouse colitis model, 22f significantly mitigated disease symptoms and histopathological damage. Overall, this study validated the potential of hydrazide-based HDAC6 PROTAC molecules for the treatment of inflammatory bowel disease.